1. Promotion of bone morphogenetic protein signaling by tetraspanins and glycosphingolipids.
- Author
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Liu Z, Shi H, Szymczak LC, Aydin T, Yun S, Constas K, Schaeffer A, Ranjan S, Kubba S, Alam E, McMahon DE, He J, Shwartz N, Tian C, Plavskin Y, Lindy A, Dad NA, Sheth S, Amin NM, Zimmerman S, Liu D, Schwarz EM, Smith H, Krause MW, and Liu J
- Subjects
- Amino Acid Sequence, Animals, Bone Morphogenetic Proteins genetics, Caenorhabditis elegans genetics, Caenorhabditis elegans Proteins antagonists & inhibitors, Caenorhabditis elegans Proteins genetics, Gene Expression Regulation, Genes, Reporter, Genetic Markers, Molecular Sequence Data, Mutation, Phenotype, Sensitivity and Specificity, Sequence Analysis, DNA, Tetraspanins genetics, Transcription Factors antagonists & inhibitors, Transcription Factors genetics, Transcription Factors metabolism, Transforming Growth Factor beta genetics, Transforming Growth Factor beta metabolism, Bone Morphogenetic Proteins metabolism, Caenorhabditis elegans Proteins metabolism, Glycosphingolipids pharmacology, Signal Transduction, Tetraspanins metabolism
- Abstract
Bone morphogenetic proteins (BMPs) belong to the transforming growth factor β (TGFβ) superfamily of secreted molecules. BMPs play essential roles in multiple developmental and homeostatic processes in metazoans. Malfunction of the BMP pathway can cause a variety of diseases in humans, including cancer, skeletal disorders and cardiovascular diseases. Identification of factors that ensure proper spatiotemporal control of BMP signaling is critical for understanding how this pathway is regulated. We have used a unique and sensitive genetic screen to identify the plasma membrane-localized tetraspanin TSP-21 as a key new factor in the C. elegans BMP-like "Sma/Mab" signaling pathway that controls body size and postembryonic M lineage development. We showed that TSP-21 acts in the signal-receiving cells and genetically functions at the ligand-receptor level. We further showed that TSP-21 can associate with itself and with two additional tetraspanins, TSP-12 and TSP-14, which also promote Sma/Mab signaling. TSP-12 and TSP-14 can also associate with SMA-6, the type I receptor of the Sma/Mab pathway. Finally, we found that glycosphingolipids, major components of the tetraspanin-enriched microdomains, are required for Sma/Mab signaling. Our findings suggest that the tetraspanin-enriched membrane microdomains are important for proper BMP signaling. As tetraspanins have emerged as diagnostic and prognostic markers for tumor progression, and TSP-21, TSP-12 and TSP-14 are all conserved in humans, we speculate that abnormal BMP signaling due to altered expression or function of certain tetraspanins may be a contributing factor to cancer development.
- Published
- 2015
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